In this project, we seek to add to the body of literature demonstrating the benefits of methadone maintenance, and to enhance those benefits. We have completed a study to evaluate whether menstrual cycles become more regular during methadone maintenance. While heroin?s menstrual disruption has been demonstrated, there are few published data concerning methadone maintenance and menstrual function. We retrospectively examined data from 191 drug-using women from two clinical trials, lasting 25-29 weeks; each woman was maintained on 70-100 mg of methadone. Start/end dates of each menses were collected. Patterns of menstruation were classified as regular, irregular, transient amenorrhea, persistent amenorrhea, or cycle restart. Repeated-measures regression modeling was used to determine correlates of cycle length and predictors of long cycles (>40 days) and short cycles (<20 days). Bleeding episodes (days from ?start? to ?stop?) were defined as one or more bleeding days, bound by at least two non-bleeding days. Correlates/predictors examined were body mass index, drug use, methadone dose, and race. In the 133 women for whom menstrual patterns could be determined, cycle-length irregularity was common; the patterns seen were: irregular, 62 (46.7%); regular, 37 (27.8%); cycle restart, 16 (12%); persistent amenorrhea, 11 (8.3%); transient amenorrhea, 7 (5.3%). Each additional week on methadone maintenance was associated with decreased risk of long (OR=0.96, p=0.001 and short (OR=0.92, p=0.001) cycles. Of 27 women with secondary amenorrhea pre-study, 16 (59%) restarted menses while maintained on methadone. Positivity for opioids or cocaine was not significantly associated with short or long cycles. Thus, cycle length begins to normalize during methadone maintenance, and menses resumption may occur. Methadone maintenance, despite interfering with menstrual function in an absolute sense, may interfere less than illicit heroin abuse. We are also conducting methodological studies to refine our monitoring of drug use and dose adequacy. For example, we are investigating the relationships among the concentrations of free and protein-bound enantiomers of methadone and its major metabolite EDDP in plasma and saliva. Our collaborators have developed new assays for these purposes and are now analyzing specimens from one of our completed clinical trials. We will determine associations among analyte concentrations, methadone dose, and treatment outcome. Our findings in this project may contribute to our therapeutic drug monitoring as we begin another large clinical trial in which flexible, individualized daily methadone doses are compared double-blind to fixed high doses?a comparison that has never been systematically made.